DESCRIPTION The long-term goal of this proposal is to understand the mechanisms of human immunodeficiency virus (HIV)-induced central nervous system (CNS) disease in AIDS. Approximately 20% of HIV-1-infected patients develop neurologic disease. The mechanisms involved in CNS pathology are unclear, since neurons do not appear to be directly infected. Indirect CNS injury may result from the release of neurotoxic cellular or viral proteins, from immune processes, or via secretion or neurotoxic metabolites. In addition, perturbations of the blood-brain barrier (BBB) have been reported in AIDS patients. Infected cells may traffic through the BBB and introduce virus and/or viral proteins into the CNS. Alternatively, infection of brain endothelial cells may cause BBB dysfunction. In this project we propose to use simian immunodeficiency virus (SIV) to investigate mechanisms of SIV neuroinvasiveness and pathogenesis. We have developed techniques to isolate brain microvascular endothelial cells (BMEC) from macaques and have elaborated an in vitro model of BBB using a flow cartridge system. This novel system will be utilized to analyze the viral sequence of SIV neuroinvasive strains which mediate entry into BMEC. The differences between env of neuroinvasive versus non-neuroinvasive viruses will be exploited in terms of mapping viral genetic determinants of both BMEC entry (gp120) and pathogenicity (gp41). In addition, the vitro BBB model will be used to study viral persistence in the brain. The viral mutants generated in mapping studies will be utilized to study the ability of SIV to abrogate the integrity of BBB in this in vivo model. BBB physiology during SIV infection will be evaluated.